Choice of Cancer Chemotherapy u Is it a science, art or voodoo medicine?

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1 PRINCIPLES OF CYTOTOXIC CHEMOTHERAPY Dr.Erdem Göker Ege Üniversitesi Tıp Fakültesi TÜLAY AKTAŞ ONKOLOJİ HASTANESİ

2 Choice of Cancer Chemotherapy u Is it a science, art or voodoo medicine?

3 BEST Tx OF CANCER

4 Historically most anticancer agents have been used without an understanding of their mechanism of action. However the potential rewards of such understanding are enormous, for the practical application of the drug, the discovery of more selective agents, and for fundamental knowledge. GeorgeHitchings, Hitchings,1968

5 An overview Role of chemotherapy in treatment of cancers Scientific basis of anticancer therapy Major classes of anti-cancer drugs Common toxicities Choice of chemotherapy: Principles and examples

6 Role of anti-cancer drugs Curative intent (30%) Chemotherapy alone (5%) Adjuvant chemotherapy (15%) Neo-adjuvant chemotherapy (5%) Chemoradiotherapy (5%) Palliative intent (70%)

7 Therapeutic Endpoints Efficacy without toxicity Palliative therapy Efficacy AND toxicity Curative therapy Toxicity without efficacy Tentative administration Drug Resistance Neither toxicity nor efficacy

8 An overview Role of chemotherapy in treatment of cancers Scientific basis of anticancer therapy Major classes of anti-cancer drugs Common toxicities Choice of chemotherapy: Principles and examples

9 Scientific basis of cancer chemotherapy The concept of tumor growth and detection The concept of log-cell kill The concept of dose intensity and density The concept of drug resistance.

14 Therapeutic Principles Diagnosis & Drug Selection I N P U T Absorption Distribution Metabolism Elimination Toxicity &/OR Efficacy Pharmacokinetics Pharmacodynamics

15 Pharmacokinetic End Points Peak drug concentration AUC (Concentration X Time) Time above target concentration Cumulative dose or cumulative AUC Dose intensity

16 Peak Concentration Concentration

17 Intensity / Time Above Concentration

18 Pharmacokinetic Patterns Absorption Activation Distribution Elimination

19 Absorption Oral Variable concentration X time profile Typical factors affecting oral absorption Presence of food Concurrent disease Likely produces a different efficacy / toxicity profile Etopside oral vs. IV Oral Fluoropyrimidines Oral Vinorelbine

20 Absorption Intramuscular VERY few anti-cancer drugs can be given this way Cytotoxicity associated with tissue damage at injection site Used by this route: Hormonals (leuprolide, glucocorticoids) L-asparaginase (lower toxicity than IV)

21 Activation Hepatic e.g. cyclophosphamide, doxorubicin, daunorubicin, others Intracellular phosphorylation e.g fludarabine Tissue metabolism with free radical production e.g. doxorubicin

22 Distribution Most target intra-cellular sites Combination solubility (water:lipid) Small number penetrate blood-brain brain barrier Protein binding High protein binding increases interaction potential May or may not limit tissue penetration Consider both plasma and tissue proteins

23 Distribution Active Metabolite distribution Ifosfamide metabolites cross blood- brain barrier Consider local factors Tumor vascularity P-glycoprotein cell membrane pump (drug efflux pump)

24 Elimination Hepatic Metabolism P450 metabolism Catabolism (especially anti-metabolites) Normal degradation pathways for amino acids etc. to carbon dioxide and water Hydrolysis Renal elimination unchanged

25 Dosing Chemotherapeutics What are we really doing in patients? Dosing for palliation in most cases Critiquing dose regimes with more emphasis on toxicity than efficacy Specifics of the approach to dosing become more important as the therapy becomes more aggressive.

26 Dosing Chemotherapeutics Traditional dosing on Body Surface Area Correlates with metabolic rate, volume of distribution Correlation with tissue concentrations? Efficacy and toxicity Extrapolated (with enthusiasm from human dose recommendations) Probably correct for SOME and not ALL protocols

27 Dosing Chemotherapeutics Body surface area mg/kg Total dose Dose to pharmacokinetic target AUC, Peak, etc. Implies therapeutic monitoring for chemotherapeutics

28 Dose Form Manipulation Liposomes Drug contained in lipid spheres Essentially artificial liposomal membranes Actively acquired by some cell lines Improved therapeutic index Reduced cardiotoxicity Enhanced activity

29 Dose Form Manipulation Chemoembolization Arterial infusion of methylcellulose micro-capsules capsules filled with chemotherapeutics Implantible polymers Surgical implantation of biodegradeable polymers containing chemotherapeutics

30 Reasons for failure of anti-cancer chemotherapy *Drug resistance: De novo or acquired *Lack of selectivity: Between normal and cancer cells *Cytokinetics: Low growth fraction of cancer *Pharmacokinetics: Poor bioavailability *Sanctuary sites: Central nervous system.

31 An overview Role of chemotherapy in treatment of cancers Scientific basis of anticancer therapy Major classes of anti-cancer drugs Common toxicities Choice of chemotherapy: Principles and examples Interview with a cancer survivor.

32 An overview: Mechanisms of action of anticancer drugs DNA, RNA & proteins are targets of anticancer drugs

33 Cell Cycle Specific Agents Antimetabolites Bleomycin Podophyllin Alkaloids Plant Alkaloids Cell Cycle Non- Specific Agents Alkylating Agents Antibiotics Cisplatin Nitrosoureas

34 Major classes of anti-cancer drugs *Alkylating agents *Antimetabolites *Natural products/antibiotics *Hormones *Molecularly-targeted therapy.

35 Alkylating Agents Mechanism of Action Alkylate within DNA at the N7 position of guanine Resulting in miscoding through abnormal base-pairing with thymine or in depurination by excision of guanine residues, leading to strand breakage Cross-linking of DNA and ring cleavage may also occur

37 Alkylating Agents Mechanism of Action

38 Alkylating agents *Mechlorethamine (Nitrogen mustard): A component of MOPP for Hodgkin s lymphoma *Cyclophosphamide (Cytoxan): A component of CMF, AC, CHOP.

39 Alkylating agents: Examples

40 Nitrogen Mustards Cyclophosphamide Ifosfamide Mechlorethamine Melphalan Chlorambucil

41 Cyclophosphamide Metabolism

42 Alkylating-Related Agents Procarbazine Dacarbazine Altretamine Cisplatin Carboplatin

43 Alkylating agents *Cisplatin: Highly emetogenic; may cause renal dysfunction, neuropathy, hearing loss A component of PEB for testicular cancer *Carboplatin: An analog of cisplatin with less side-effects.

44 Platinum Coordination Complexes These compounds alkylate N7 of guanine. They cause nephro- and ototoxicity. To counteract the effects of nephrotoxicity, give mannitol as an osmotic diuretic, or induce chloride diuresis with 0.1% NaCl.

45 Antimetabolites SFolate analogs SPyrimidine analogs SPurine analogs.

46 What are Antifolates? Substances that interfere with the action of folate intermediates are known as antifolates Can be divided into three basic categories based on the enzyme they inhibit Dihydrofolate Reductase (DHFR) Serine Hydroxymethyl Transferase Thymidylate Synthase

47 Dihydrofolate Reductase Antifolates H 2 N N N HN N H N HOOC O O COOH Target molecules for inhibiting this enzyme must be structurally similar to Folic Acid

48 Serine Hydroxymethyl Transferase Antifolates H 2 N HN N O H N N H H H H N R Tetrahydrofolate Must have structural similarities to THF

49 Thymidylate Synthase Antifolates O H H 2 N N H N O HN N HN O N H 2 C N R -2 O 3 PO H 2 C HO O Uracil N 5,N 10 -Methylene-THF Target antifolates that inhibit this enzyme must have structural similarities to Uracil or the cofactor

50 O COOH N H N N HOOC N N CH 3 H 2 N N NH 2 Methotrexate (MTX) Clinically available in 1953 Still the most widely used drug in chemotherapy Therapeutic index of 1 Dihydrofolate reductase inhibitor

51 Antifolates Utilised since 1940 in the treatment of cancer Methotrexate standard in regimens for: Neoplastic Diseases: ALL, NHL, Osteosarcoma, Breast Ca, Head&Neck, Choriocarcinoma Non-neoplastic: neoplastic: Rheumatoid Arthritis, GVHD Cellular resistance to MTX is frequent Other antifolates: Trimetrexate, Edatrexate, Raltitrexed, Pemetrexed

53 TRANSPORT

54 How Drugs Get Into Cells Diffusion Transport Endocytosis D D D D D D D e.g., vinblastine, doxorubicin e.g., nucleoside analogs e.g., immunotoxins

56 Mechanisms of Folate Transport Influx Folate Receptors -activates an energy dependent, endocytic pathway. Reduced Folate Carrier -bidirectional anion exchange mechanism. Low ph folate transporter (?) (Biochem Pharmacol 53;223-31, 31, 1997). Efflux At least two energy dependent efflux systems have been identified (Biochem Pharmacol 51;975-82, 1996).

57 POLYGLUTAMYLATION

58 Purine Biosynthesis GAR and AICAR Transformylase FH 4 MTX FPGS MTX MTX (glu) n DHFR CHFH 2 4 dump FH 2 TS MTX MTX Lysosome GGH TMP CELL MEMBRANE EXTRACELLULAR INTRACELLULAR

59 STUDYING POLYGLUTAMYLATION Functional Assay: Using H 3 -MTX and HPLC Enzyme Study: Levels of Folylpolyglutamyl Synthase (FPGS) and Gamma Glutamyl Hydrolase (GGH) Molecular Studies: Expression and Mutational Screen for FPGS and GGH

60 Therapeutic Implications of Methotrexate Studies Administering high dose methotrexate is expensive and results in morbidity/mortality. Trimetrexate an inhibitor of dihydrofolate reductase is transported into cells by a different mechanism. Trimetrexate with simultaneous leucovorin is safe and effective in the treatment of human transport defective leukemia cell lines xenografted into SCID mice.

61 High-Dose Methotrexate in Osteosarcoma Standard treatment is high-dose therapy as data suggests it is more effective than conventional dose. The literature suggests it is the peak level not the AUC that correlates with therapeutic response in osteosarcoma. The peak level is predominantly determined by dose. Ferrari S, et al: J Chemother 5:135-41, 1993 Graf N, et al: J Clin Oncol 12: , 1994 Delepine N, et al: Anticancer Res 15:489-94, 94, 1995 Bacci G, et al: J Clin Oncol 16:658-63, 63, 1998 Others Impairments in methotrexate transport are frequent in osteosarcoma tumor samples, which can be overcome by achieving a high peak level.

62 Pyrimidine Antagonists Fluorouracil Cytarabine Gemcitabine Capecitabine

63 Pyrimidine analogs: 5-Fluorouracil Cytosine arabinoside (Ara-C) (5-FU) Gemcitabine

64 Activation of 5-FU

65 Mechanism of Action 5-FU 5-FU inhibits thymidylate synthase therefore causing depletion of Thymidylate 5-FU is incorporated into DNA 5-FU inhibits RNA processing

66 Pyrimidine analogs 5-Fluorouracil (5-FU) Inhibits thymidylate synthase A component of CMF in the treatment of breast cancer Capecitabine (Xeloda): given orally Tegafur (UFT) Cytosine arabinoside (Ara-C) Inhibits DNA polymerase Therapy for AML Gemcitabine (Gemzar) Analog of Ara-C Therapy for solid tumors, i.e. pancreatic cancer.

67 Pemetrexed Continuing his work with the synthesis of antifolate molecules, Edward C. Taylor has synthesized the drug known as Pemetrexed in O O NH HN CO 2 H H 2 N N N H CO 2 H

68 Pemetrexed This is a unique antifolate in that it has been shown to inhibit at least five of the major folate-dependent enzymes thymidylate synthase dihydrofolate reductase glycinamide ribonucleotide formyltransferase aminoimidazole ribonucleotide formyltrasnferase C-1 tetrahydrofolate synthetase Pemetrexed is an extraordinarily effective anti-tumor tumor agent.

70 Purine analogs: Fludarabine 2-Chlordeoxyadenosine

71 Purine analogs 2-Chlorodeoxyadenosine (Cladribine) Curative treatment for hairy cell leukemia Fludarabine (Fludara) Therapy for CLL and low-grade lymphoma.

72 Purine Antagonists Mercaptopurine Thioguanine Fludarabine Phosphate Cladribine

73 Mercaptopurine/Thioguanine Must metabolized by HGPRT to the nucleotide form This form inhibits numerous enzymes of purine nucleotide interconversion

76 Gemcitabine Gemcitabine is S-phase specific it is a deoxycytidine antimetabolite it undergoes intracellular conversion to gemcitabine monophosphate via the enzyme deoxycytidine kinase it is subsequently phosphorylated to gemcitabine diphosphate and gemcitabine triphosphate

77 Gemcitabine Gemcitabine triphosphate competes with deoxycytidine triphosphate (dctp) for incorporation into DNA strands do to an addition of a base pair before DNA polymerase is stopped, Gemcitabine inhibits both DNA replication and repair Gemcitabine-induced induced cell death has characteristics of apoptosis

78 Natural Products/Antibiotics SAnthracyclines SAntimitotic drugs SEpipodophyllotoxins SCamptothecins SBleomycin.

79 Natural Products/Antibiotics: Anthracyclines Mechanisms of action: DNA intercalation and inhibition of topoisomerase II --- double-strand DNA breaks Toxicity: Irreversible cardiomyopathy (> 500 mg/m2).

80 Anthracyclines Mechanism of Action High-affinity binding to DNA through intercalation, resulting in blockade of DNA and RNA synthesis DNA strand scission via effects on Top II Binding to membranes altering fluidity Generation of the semiquinone free radical and oxygen radicals

81 Mitoxantrone Structure resembles the anthracyclines Binds to DNA to produce strand breakage Inhibits DNA and RNA synthesis Treats pediatric and adult acute myelogenous leukemia, non-hodgkin s lymphomas, and breast cancer Causes cardiac toxicity

82 Mitomycin Mechanism of Action Bioreductive alkylating agent that undergoes metabolic reductive activation through an enzyme-mediated mediated reduction to generate an alkylating agent that cross-links DNA

83 *

84 Natural Products/Antibiotics: Antimitotic agents By interfering microtubule synthesis and degradation, these compounds inhibit cell division.

85 Antimitotics: Taxanes

86 Natural products/antibiotics: Antimitotics Paclitaxel (Taxol): Stabilizes microtubules Causes alopecia totalis, neuropathy Docetaxel (Taxotere): Stabilizes microtubules.

87 Natural Products/Antibiotics: Antimitotics Vinorelbine Vinblastine Vincristine Inhibits polymerization of microtubules.

88 Vinca Alkaloids Mechanism of Action Binds to the microtubular protein tubulin in a dimeric form The drug-tubulin complex adds to the forming end of the microtubules to terminate assembly Depolymerization of the microtubules occurs Resulting in mitotic arrest at metaphase, dissolution of the mitotic spindle, and interference with chromosome segregation CCS agents-m phase

89 Topoisomerases: Cleavage, unwinding and re-annealing of DNA *

90 Natural Products/Antibiotics: Epipodophyllotoxin Etoposide (VP-16): Inhibits topoisomerase II leading to double-strand DNA breaks A component of PEB for testicular cancer.

91 Natural Products/Antibiotics: Camptothecins Topotecan (Hycamtin) & Irinotecan (CPT-11, Camptosar): Inhibits topoisomerase I resulting in singlestrand DNA breaks.

92 Camptothecins Topotecan Irinotecan

93 Camptothecins Mechanism of Action Interfere with the activity of Topoisomerase I Resulting in DNA damage Irinotecan- a prodrug that is metabolized to an active Top I inhibitor, SN-38

95 Natural Products/Antibiotics: Peptide antibiotic Bleomycin Induces DNA strand breaks May cause pulmonary fibrosis A component of PEB.

96 Bleomycin Acts through binding to DNA, which results in single and double strand breaks following free radical formation and inhibition of DNA synthesis The DNA fragmentation is due to oxidation of a DNA-bleomycin-Fe(II) complex and leads to chromosomal aberrations CCS drug that causes accumulation of cells in G 2

97 Carmustine Lomustine Semustine Nitrosoureas Streptozocin-naturally naturally occuring sugar containing M.O.A.- cross-link through alkylation of DNA All cross the blood brain barrier

98 Podophyllotoxins Etoposide (VP-16) Teniposide (VM-26) Semi-synthetic derivatives of podophyllotoxin extracted from the root of the mayapple

99 Podophyllotoxins Mechanism of Action Blocks cells in the late S-G 2 phase of the cell cycle through inhibition of topoisomerase II Resulting in DNA damage through strand breakage induced by the formation of a ternary complex of drug, DNA, and enzyme

100 Miscellaneous AntiCancer Agents Asparaginase Hydroxurea Mitoxantrone Mitotane

101 An analog of urea Hydroxyurea Inhibits the enzyme ribonucleotide reductase Resulting in the depletion of deoxynucleoside triphosphate pools Thereby inhibiting DNA synthesis S-phase specific agent Treats melanoma and chronic myelogenous leukemia

102 An overview Role of chemotherapy in treatment of cancers Scientific basis of anticancer therapy Major classes of anti-cancer drugs Common toxicities. Choice of chemotherapy: Principles and examples Interview with a cancer survivor.

103

104 Common toxicities of chemotherapy Organs with active cell division are affected: *Bone marrow *GI tract mucosa * Hair follicles These side-effects are often reversible.

105 Common toxicity Bone marrow suppression: Leukopenia, thrombocytopenia and anemia Nadir WBC count typically occurs 7-14 days after treatment Caused by most anti-cancer drugs except: Bleomycin, vincristine, hormones, and most of the molecularly-targeted agents.

106 Common toxicity *Gastrointestinal toxicity: -Nausea and vomiting: Especially cisplatin, mechlorethamine, anthracyclines -Diarrhea: 5-FU, topotecan, irinotecan -Mucositis: 5-FU *Alopecia (Hair loss): -Paclitaxel, carboplatin, anthracyclines etc.

107 Common toxicity *Renal toxicity: Cisplatin *Pulmonary toxicity: Bleomycin (pulmonary fibrosis) *Peripheral neuropathy: Cisplatin, paclitaxel, vincristine.

108 Long-term complications *Cardiomyopathy: Anthracyclines (Incidence exceeds 5% for doxorubicin dose > 500 mg/m2) *Leukemia: Mechlorethamine, high-dose etoposide *Infertility: Alkylating agents causing azoospermia.

109 Prevention and treatment of side-effects of anticancer drugs Most of the side-effects can be effectively prevented and treated.

110 An overview Role of chemotherapy in treatment of cancers Scientific basis of anticancer therapy Major classes of anti-cancer drugs Common toxicities Choice of chemotherapy: Principles and examples. Interview with a cancer survivor.

111 Principles for choice of anticancer drugs u u u u Cancer type and stage Curative or palliative intent Patient status: Performance status, co- morbid conditions, organ functions Combination of drugs is the choice.

112 Principles of Combined Chemotherapy Each drug is active against the cancer Each drug has a different mechanism of action Each drug has a different mechanism of resistance Non-overlapping overlapping toxicities among the drugs Synergism and safety.

113 Principles of Combined Chemotherapy Adoption of a new regimen -Requires randomized clinical trials: Phase III study -A comparison of the new regimen with the standard therapy.

114 Examples of combined chemotherapy Non-Hodgkin s lymphoma (NHL): CHOP Relapsed non-hodgkin s lymphoma: High-dose chemotherapy followed by autologous peripheral stem cells or bone marrow transplant Testicular cancer: PEB.

115 Success Stories of Clinical Trial Investigation Cure Rates Limitation of Toxicity Reduction of Treatment Duration Lower Treatment Intensity

116 Historically most anticancer agents have been used without an understanding of their mechanism of action. However the potential rewards of such understanding are enormous, for the practical application of the drug, the discovery of more selective agents, and for fundamental knowledge. GeorgeHitchings, Hitchings,1968

2. Mitotic Spindle Inhibitors (modulators of tubulin polymerisation) 3. Antimetabolites (anti-folates, pyrimidine and purine analogues)

CANCER DRUG CLASSES The classes of drugs currently used in the cancer clinic are 1. DNA Binding Agents (intercalating and alkylating agents) 2. Mitotic Spindle Inhibitors (modulators of tubulin polymerisation)